GEN Exclusives

China Dispatch: Pseudoxanthoma Elasticum

Sharon Terry, president and CEO of the Genetic Alliance, attends a seminar on the genetic condition PXE in Xi’an.

Terry and others are establishing a PXE International Center for Research and Clinical Care at the Xijing Hospital Fourth Military Medical University.

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GEN’s China Dispatches are issued by Sharon F. Terry, president and CEO of the Genetic Alliance, a network of more than 10,000 organizations, including 1,200 disease-advocacy organizations, that enables individuals, families, and communities to reclaim their health and become full participants in translational research and services. A pioneer of consumer participation in genetics research, services, and policy, Sharon F. Terry serves a leadership role not only at the Genetic Alliance, but also at the Genetic Alliance Registry and Biobank and at PXE International, a research advocacy organization for the genetic condition pseudoxanthoma elasticum (PXE). After a thoughtful hike up Hua Mountain,Terry visits a hospital in Xi’an to attend a seminar on PXE.

Today is dedicated entirely to pseudoxanthoma elasticum (PXE) and PXE International. We are at the Xijing Hospital Fourth Military Medical University in Xi’an where we are establishing a PXE International Center for Research and Clinical Care. This is the culmination of a year of collaboration, begun when we visited here last November. We are delighted to meet the vice president of the hospital, and to reunite with our friend Professor Gang Wang, M.D., Ph.D., the chief of the new center, and the head of the department of dermatology.

Our initial collaboration was focused on mutation detection in Chinese affected by PXE. Dr. Wang’s lab has worked up 29 patients in partnership with Jouni Uitto’s lab at Jefferson. In fact, Jie will stay here when we leave tomorrow to work with the researchers here on further classifying the mutations.

Jouni, Jie, and Liang Jin gave a seminar this morning to our new center’s staff. They described basic issues of PXE and then got into the details, including those that elude our understanding. The gene is primarily expressed in the liver and kidney. The pathophysiology is unknown, but these missense and nonsense mutations, and a few deletions, result in mineralization of the mid-dermis of the skin, the membrane behind the eye, and mid-laminar layer of mid-sized arteries (a whole lot of “mids”). The transmembrane protein appears to be unable to shuttle an unknown substance out of the cell, resulting in this peripheral tissue mineralization. The clinical result, for our children and the 4,000 other people we have on our registry, varies greatly, as is true for many Mendelian disorders. Individuals present with lax and redundant skin (wrinkly) in the flexor areas, vision loss like macular degeneration, intermittent claudication, and gastrointestinal bleeding. This is essentially a very slow aging disease since most of these signs and symptoms appear in the second decade and beyond. Most people lose their vision in their 40s.

Jie gave an exciting talk about her work with premature codon read-through in the ABCC6 gene, using the drug PTC124 [can link to any articles you have done on this or PTC Therapeutics] in mice. Jie’s results are interesting, but not definitive. Following Jie’s talk, Liang Jin reported on his work analyzing mutations in Chinese PXE patients. He has found a large number of novel, as yet unreported, mutations. In a few cases, it is not clear if PXE progresses in the same manner in Chinese patients as it does in those of European decent. We know that environment has an enormous effect on the condition, and so we may be seeing the effects of different diet and lifestyle.

The questions from the audience of clinicians, researchers, and students were very astute. These led to a discussion about Mark Lebwohl’s magnesium clinical trial at Mt. Sinai Hospital in NY. We hope that work the Uitto group has done in mice will be replicable in humans. The discussion continued most of the day in a variety of settings, and together we explored the major questions in PXE: why it has late onset, why many more woman are affected than men, why there are skin findings only in the flexor areas, identifying the substrate, and why clinical expression is limited to only select elastin tissue in certain organs. It is fabulous to have these great minds joining ours to puzzle this out. Interestingly, the common mutations we have found in the rest of the world (the R1141X mutation occurs in ~30% of the people we have sequenced so far, mostly those of European descent), are not common in the Chinese. We do see some potential hotspots but need more than the people screened in Chinese so far.

International collaboration is important for all diseases, particularly rare ones. PXE is only an example of thousands of other diseases. Here, just as in Beijing and Shandong, researchers are hungry for collaboration. I think we can facilitate partnership both in this experiment with a rare condition (PXE), and more broadly for Genetic Alliance’s many network members. So much of collaboration is simply relationship building. Being face-to-face makes an enormous difference in our ability to gain each other’s trust, and plan productive next steps. The intense and clear desire of the young clinicians to alleviate the suffering of their patients is the best driver and will keep all of our eyes on the prize.

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